title: Potential of novel antiretrovirals to modulate expression and function of drug transporters in vitro.
abstract: OBJECTIVE
  The chemokine receptor antagonists maraviroc and vicriviroc and the integrase inhibitors elvitegravir and raltegravir are novel antiretroviral agents for the treatment of HIV-1 infections. ATP-binding cassette (ABC) transporters as modulators of the effectiveness and safety of therapy can mediate viral resistance and drug-drug interactions. To expand knowledge on drug-drug interactions of these antiretrovirals we investigated whether these compounds are substrates, inhibitors or inducers of important ABC transporters.
  
  
  METHODS
  We evaluated P-glycoprotein (P-gp/ABCB1) inhibition by the calcein assay in P388/dx and L-MDR1 cells, breast cancer resistance protein (BCRP/ABCG2) inhibition in MDCKII-BCRP cells by pheophorbide A efflux, and inhibition of the multidrug resistance-associated protein 2 (MRP2/ABCC2) by using the MRP2 PREDIVEZ™ Vesicular Transport Kit. Substrate characteristics were evaluated by growth inhibition assays in MDCKII cells overexpressing particular ABC transporters. Induction of transporters was quantified by real-time RT-PCR in LS180 cells and for ABCB1 also at the functional level.
  
  
  RESULTS
  Elvitegravir and vicriviroc inhibited ABCB1 in P388/dx and L-MDR1 cells (f2 values 1.9±0.2 µmol/L and 8.5±3.6 µmol/L, respectively). The IC50 for ABCG2 inhibition was 15.7±5.7 µmol/L for elvitegravir and 236.7±93.3 µmol/L for vicriviroc. Raltegravir and maraviroc showed no evidence of ABCB1 or ABCG2 inhibition. Maraviroc and vicriviroc stimulated ABCC2 transport function. Growth inhibition assays suggest that elvitegravir, raltegravir and vicriviroc are substrates of ABCB1. Induction assays demonstrate that mRNA expression of several ABC transporters is induced by these antiretrovirals in LS180 cells.
  
  
  CONCLUSIONS
  The new antiretrovirals bear the potential to modulate expression and function of several ABC transporters, with elvitegravir revealing the highest interaction potential.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Nadine Cécile Luise
authors.initials: NC
authors.lastname: Zembruski
authors.forename: Gabriele
authors.initials: G
authors.lastname: Büchel
authors.forename: Lisa
authors.initials: L
authors.lastname: Jödicke
authors.forename: Melanie
authors.initials: M
authors.lastname: Herzog
authors.forename: Walter Emil
authors.initials: WE
authors.lastname: Haefeli
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D044966:Anti-Retroviral Agents / Q000378:metabolism* / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003510:Cyclohexanes / Q000378:metabolism / Q000494:pharmacology; D004285:Dogs; D020869:Gene Expression Profiling; D000077592:Maraviroc; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology; D011760:Pyrrolidinones / Q000378:metabolism / Q000494:pharmacology; D015363:Quinolones / Q000378:metabolism / Q000494:pharmacology; D000068898:Raltegravir Potassium; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D044966:Anti-Retroviral Agents; D003510:Cyclohexanes; D010879:Piperazines; D011743:Pyrimidines; D011760:Pyrrolidinones; D015363:Quinolones; D014230:Triazoles; D000068898:Raltegravir Potassium; C509700:elvitegravir; D000077592:Maraviroc; C486781:vicriviroc